The invention relates to cell markers that are useful in detecting disease; it relates particularly to cell markers that are useful in identifying epithelial cells and determining the differentiation status of normal and malignant epithelial cells.
The identification and characterization of epithelial cell markers is pursued in efforts to understand the biology of tissue differentiation and to diagnose and monitor carcinomas resulting from the malignant transformation of epithelial tissues.
Efforts to reduce the mortality resulting from breast cancer include the identification of breast tissue specific antigens, which are potentially useful in non-invasive methods leading to the early diagnosis of the disease and reliable follow up after surgical removal of tumors; they should also prove useful as well as a tool of basic research directed to breast cancer biology.
The use of high-prevalence, specific human mammary epithelial antigens (HME-Ags) as breast cancer markers has been proposed (Ceriani, et al., 1982); Sasaki et al., 1985). These antigens are localized in the plasma membranes of breast epithelial cells, whether the cells are normal or neoplastic, and they occur in all neoplastic breast cells. The antigens are normally released from the epithelial cells in the human milk fat globule membrane, but are also released into the circulation by mammary tumors. Breast cancer patients therefore have high levels of HME-Ags in circulating plasma, while patients with disseminated nonbreast cancer and normal females do not. Circulating antigens are found to have molecular weights of 150,000, 70,000, and 46,000 daltons.
A group of well characterized markers for epithelial cells of all tissue types is a family of proteins known as cytokeratins (Fuchs, 1988). Cytokeratins are the intermediate filament proteins of epithelial cells, and their presence is a definitive proof that the cells under study are of epithelial type; however, there are different members of cytokeratins, and their expression has been shown to be variable, and dependent on several parameters, including the tissue type and state of differentiation, so that their expression patterns may be complex and difficult to interpret. Another epithelial marker, epithelial membrane antigen, has been defined only in terms of immunological reactivity, which resides in the large (50%) carbohydrate moiety of the glycoprotein (Pinkus, et al, 1985). The primary use of this marker has been in distinguishing between tumors of epithelial and non-epithelial origin in histopathological sections, but it appears to be expressed also on various normal tissues of mesodermal origin, including fibroblasts (Imrie, et al., 1990). Cloning of the mRNA coding for the protein has not been reported.
It would be useful to identify a discrete epithelial cell specific marker that reliably follows cell differentiation, is not organ or tissue specific, but cell origin specific, and is associated only with epithelial cells, and not with cells from the fibroblast or lymphoid lineage. This marker could therefore be used to follow the extent of differentiation of epithelial cells or the extent of de-differentiation that occurs on neoplastic transformation. A specific epithelial cell marker could also determine whether tumors are of epithelial origin or not, a distinction which is often important in therapy.